FR2742155A1 - USE OF HETEROAROMATIC AND TRICYCLIC DERIVATIVES OF 1,4-DIHYDRO-1,4-DIOXONAPHTHALENE, NOVEL COMPOUNDS OBTAINED AND THEIR USE IN THERAPEUTICS - Google Patents

Abstract

The therapeutical use of tricyclic nitrogen-containing derivatives and pharmaceutically acceptable salts thereof having general formula (I), for treating diseases related to venous function deficiency and/or inflammatory oedema, is disclosed. In general formula (I), A is a sulphur or oxygen atom or a radical R3N where R3 is a hydrogen atom, a C1-5 alkyl radical or an optionally substituted aromatic or heteroaromatic ring; each of X1, X2, X3 and X4 is independently a carbon atom or a nitrogen atom; R1 is a C1-5 alkyl radical, an optionally substituted aromatic ring or an optionally substituted heteroaromatic ring having one or more heteroatoms; and R2 is a hydrogen atom or a C1-5 alkyl radical.

Description

 The present invention relates to the use of nitrogen tricyclic derivatives and their pharmaceutically acceptable salts for the production of a medicament for the treatment of diseases related to impaired venous function and / or inflammatory edema. and the new compounds obtained. It relates more particularly to the heteroaromatic and tricyclic derivatives of 1,4-dihydro-1,4-dioxonaphthalene. The invention relates to the therapeutic application of all these compounds.

It is described in US Patent 3,084,165, by
Schellhammer CW, Petersen S., Domagk G. synthesis of 2-substituted derivatives of imidazo [4,5-g] quinolines from 6,7-diamino-5,8-dihydro-5,8-dioxo - quinolines and aldehydes.

 Collect article. Czech. Chem. Common. 56 (9), 19191925 (1991) by Yanni AS describes the synthesis of new quinone heterocyclic derivatives from 6-chloro-5,8-dihydro-5,8-dioxoquinoline hydrochloride, in particular by reaction with a amide, thiourea, semicarbazide or thiosemicarbazide.

 The document Ann. 624, 108-119 (1959) by Schellhammer C. W., Petersen S shows the preparation of tricyclic derivatives from 6,7-dihalo-5,8-dihydro-5,8-dioxoquinolines.

Finally the patent DE 1,137,022 of Schellhammer CW,
Koenig HB, Petersen S., Domagk G. describes the preparation of 4-substituted-4,9-dihydro-4,9-dioxothiazolo [4,5-g] quinolines by a heterocyclic derivative.

dans laquelle
A est soit un atome de soufre, d'oxygène, ou un radical R3N où R3 est un atome d'hydrogène, un radical alkyle en C1 à Cg, un cycle aromatique substitué ou non, ou un cycle hétéroaromatique substitué ou non,
X1, X2, X3, X4, sont indépendamment l'un de l'autre un atome de carbone ou un atome d'azote,
R1 est un radical alkyle en C1 à Cg, un cycle aromatique substitué ou non, ou un cycle hétéroaromatique, ayant un ou plusieurs hétéroatomes, substitué ou non,
R2 est un atome d'hydrogène, un radical alkyle en C1 à C5.The nitrogen tricyclic derivatives and their pharmaceutically acceptable salts according to the present invention correspond to the general formula

in which
A is either a sulfur atom, oxygen atom, or an R3N radical where R3 is a hydrogen atom, a C1-C8 alkyl radical, a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring,
X1, X2, X3, X4 are independently of one another a carbon atom or a nitrogen atom,
R1 is a C1-C8 alkyl radical, a substituted or unsubstituted aromatic ring, or a heteroaromatic ring, having one or more heteroatoms, substituted or unsubstituted,
R2 is a hydrogen atom, a C1-C5 alkyl radical.

The invention also relates to the novel products hereinafter
4,9-dihydro-4,9-dioxo-2- (4-fluorophenyl) -1H-imidazo [4,5-g] quinoline;
4,9-dihydro-4,9-dioxo-2- (3-pyridyl) -1H-imidazo [4,5-g] quinoline;
4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-g] quinoline;
4,9-dihydro-4,9-dioxo-2- (3-fluorophenyl) thiazolo [4,5-g] quinoline;
4,9-dihydro-4,9-dioxo-2- (4-fluorophenyl) thiazolo [4,5-g] quinoline;
2- (2,4-difluoro-phenyl) -4,9-dihydro-4,9-dioxothiazolo [4,5-g] quinoline;
4,9-dihydro-4,9-dioxo-2- (2-pyridyl) thiazolo [4,5-g] quinoline sulfate;
4,9-dihydro-4,9-dioxo-2- (3-furyl) thiazolo [4,5 g] quinoline
4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [5.4-g] quinoline
4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [5,4-glquinoline;
4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4-f] isoquinoline;
4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [5,4-f] isoquinoline;
4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-f] isoquinoline;
4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [4,5-g] quinoxaline
4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-g] quinoxaline;
4,9-dihydro-4,9-dioxo-2- (2-furyl) -7-methyl-thiazolo [4,5-g] isoquinoline.

The invention also relates to the intermediate products hereafter
7-amino-6-chloro-5,8-dihydro-5,8-dioxoisoquinoline
6-amino-7-chloro-5,8-dihydro-5,8-dioxoisoquinoline.

The invention also relates to the use of nitrogen tricyclic derivatives and their pharmaceutically acceptable salts thereof having the general formula (I) above for obtaining a medicament for
- the treatment of functional and organic venous insufficiency
- treatment of hemorrhoidal pathologies;
- the treatment of migraine
- the treatment of dermatological and cardiovascular osteoarticular inflammations
- Treatment of shock states consisting of a significant drop in blood pressure especially in septic shock states.

où
A = -NH, S, O X,, X2 X3, X4 = C ou N

Specifically, the compounds of the present invention have the following general formula (I):

or
A = -NH, S, OX, X2 X3, X4 = C or N

R2 = H, CH3
The present invention also relates to the salts of the salt-forming compounds of formula (I). These salts include the mineral acid addition salts such as hydrochloric, hydrobromic, sulfuric, phosphoric or nitric acid and the addition salts of organic acids such as acetic, propionic, oxalic, citric acid, maleic, fumaric, succinic, tartaric.

 The invention is illustrated by the nonlimiting examples below.

 The examples indicated by a number correspond to new compounds while the examples comprising a letter correspond to known compounds.

In all the examples, the analyzes are carried out as indicated below
- Melting points: They were made on a device type Kofler Bench LEICA - REICHERT model
WME.

Thin layer chromatographs: They were obtained on plates of silica gel with Wu 54 fluorescence indicator 0.25 mm thick of type
MACHEREY-NAGEL (Reference 805 023). Elution solvents are indicated for each compound.

 Mass Spectra: They were carried out with an AEI MS-50 type spectrometer. The ionization mode is indicated for each analysis.

 NMR spectra: The H and 13 C NMR spectra were carried out either on a JEOL type spectrometer respectively at 270 MHz and at 68 MHz, or on a BRUCKER type spectrometer at 400 MHz and at 100 MHz, respectively. The deuterated solvents used are indicated for each analysis.

 Infra-Red Spectra: They were obtained on a NICOLET 205 FT-IR type spectrometer. They are carried out at 1% (m / m) in dispersion in KBr.

Example 1 4,9-Dihydro-4,9-dioxo-2- (4-fluorophenyl) -1H-imidazo
[4,5-g] quinoline
To 1.0 g (5.29 mmol) of 6,7-diamino-5,8-dihydro-5,8-dioxoquinoline suspended in 15 ml of water is added at room temperature 0.567 ml (5%). 29 mmol) of 4-fluorobenzaldehyde and 1,800 ml of glacial acetic acid. The reaction is stirred for 30 minutes under reflux and the brown precipitate which forms is filtered on sintered glass and purified on cake (support: silica, eluent: dichloromethane). The solid obtained is decolorized and then recrystallized from 500 ml of methanol to give 0.8 g of 4.9 dihydro-4,9-dioxo-2- (4-fluorophenyl) -1H-imidazo [4,5-g] quinoline in the form of brown crystals.

Yield: 52%
F:> 2600C
Rf: 0.50 (CH2Cl2 / Methanol, 90/10)
MS (IE): m / z 293 (M +)
1H NMR (DMSO d6): δ (ppm) 14.48 (bs, 1H, NH) 8.97 (m, 1H, H-7) 8.43 (d, 1H, H-5, JH5-H6 = 7.94Hz) 8.27 (m) , 2H, H-2 ', H-6') 7.81 (m, 1H, H-6) 7.39 (m, 2H, H-3 ', H-5')
13 C NMR (DMSO d 6): δ (ppm) 176.47 (1 C, C = O) 160: 45 (1 C, C quat) 153.25 (1 C, C-7) 152.58 (1 C, C quat) 148.93 (1 C, C quat) 140.33 ( 1 C, C quat) 134.24 (1C, C-5) 130.07 (1C, C quat) 129.23 (2C, C-3 ', C-5') 127.43 (1C, C-6) 116.23 (1C, C quat) 116.23 and 115.90 ( 2C, C-2 ', C-6')
IR (KBr): Wu (cm) 3225 (NH); 1663, 1644 (C = O)
Example 2
4,9-Dihydro-4,9-dioxo-2- (3-pyridyl) -1H-imidazo [4,5g] quinoline
To 900 mg (4.77 mmol) of 6,7-diamino-5,8-dihydro5,8-dioxoquinoline suspended in 15 ml of water, 0.450 ml (4.77 mmol) of 3-pyridinecarboxaldehyde and 1.80 ml of glacial acetic acid. The reaction is stirred for 45 minutes under reflux and the brown precipitate which is formed is filtered on sintered glass, washed with iced water and purified on cake (silica support, eluent: dichloromethane / methanol, 98/2 to 95/5).

The solid obtained is decolorized and then recrystallized from a 98/2 dichloromethane / methanol mixture to give 700 mg of 4,9-dihydro-4,9-dioxo-2- (3-pyridyl) -1H-imidazo [4,5g]. quinoline in the form of red crystals.

Yield: 53%
F:> 2600C
Rf: 0.50 (CH2Cl2 / Methanol, 90/10)
MS (IE): m / z 276 (M +)
1H NMR (DMSO d6): δ (ppm) 14.50 (bs, 1H, NH) 9.36 (s, 1H, H-2 ') 8.97 (d, 1H, H-7, JH 6 H = 4.57Hz) 8.68 (d , 1H, H-5, JH5-H6 = 4.88Hz) 8.53 (d, 1H, H-6 ', JH5'-H6' = 8.24Hz) 8.45 (d, 1H, H-4 ', JH4'-H5' = 7.93 Hz) 7.82 (m, 1H, H-6) 7.57 (m, 1H, H-5 ')
13 C NMR (DMSO d6): # (ppm) 176.55 (1 C, C = O) 174.45 (1 C, C = O) 153.31 (1 C, C-7) 151.32 (1 C, C quat) 150.83 (1 C, C-2 ') 148.80 (1C, Cquat) 147.71 (1C, C-6') 134.32 (1C, C-5) 134.54 (1C, C-4 ') 130.14 (1C, Cquat) 127.49 (1C, C-6 ) 125.54 (1C, C quat) 124.01 (1C, C-5 ')
IR (KBr): δ (cm-1) 3104 (NH); 1660, 1646 (C = O)
Example 3
4,9-Dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-g] quinoline
To 0.80 g (3.84 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxoquinoline is added at room temperature 5.53 g (23.02 mmol) of sulfide. of sodium nonahydrate dissolved in 9.6 ml of water. After 5 minutes, 405 μl (3.84 mmol) of 2-fluorobenzaldehyde and 880 μl of glacial acetic acid are added to the blue reaction medium. The reaction is stirred for 10 minutes at 80 ° C. and the black precipitate that forms is filtered on sintered glass and then washed with ethanol. The brown solid thus obtained is taken up in 400 ml of chloroform and washed with 400 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness. The yellow product obtained is purified on cake (support: silica eluent: dichloromethane / isopropanol, 99/1) to provide 0.30 g of 4,9-dihydro -4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-g] quinoline as yellow crystals.

Yield: 25%
F:> 2600C
Rf: 0.60 (CH2Cl2 / Methanol, 97/3)
MS (IE): m / z 310 (M +)
1H NMR (CDCl3): δ (ppm) 9.04 (d, 1H, H-7, JH6-H7 = 9.55Hz) 8.63 (d, 1H, H-5, JH5-H6 = 9.54Hz) 8.52 (m, 1H, H-6 ') 7.76 (m, 1H, H-6) 7.52 (m, 1H, H-4') 7.25 (m, 2H, H-3 ', H-5')
13 C NMR (CDCl 3): δ (ppm) 176.60, 176.18 (2 C, C = O) 162.94 (1 C, C-2 ') 158.44 (1 C, C-2) 154.06 (1 C, C-7) 148.34 (1C, Cquat) 135.34 (1C, C-5) 133.58 (2C, C-6, Cquat) 129.52 (2C, Cquat, C-6 ') 127.44 (1C, C-4') 124.58 (2C, C-5 ', Cquat) ) 115.77, 115.68 (2C, C-1 'C-3')
IR (KBr): υ (cm-1) 3045 (CH); 1682, 1671 (C = O)
Example 4 4,9-Dihydro-4,9-dioxo-2- (3-fluorophenyl) thiazolo [4,5-g] quinoline
To 1.80 g (8.60 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxoquinoline is added at room temperature 12.44 g (51.70 mmol) of sulfide. of sodium nonahydrate dissolved in 22 ml of water. After 2 hours at 40 ° C., 4.14 g (17.23 mmol) of sodium sulphide nonahydrate are added to the reaction medium. This then becomes blue and 0.911 ml (8.60 mmol) of 3-fluorobenzaldehyde and 1.960 ml of acetic acid are added. The reaction is maintained for 1 hour 30 minutes at 80 [deg.] C. and the brown precipitate that forms is filtered on a sintered glass and then washed with 150 ml of ethanol. The brown solid thus obtained is taken up in 500 ml of chloroform and washed with 500 ml of chloroform. 'water. The organic phase is dried over calcium chloride and evaporated to dryness. The powder thus obtained is purified on cake (support: silica, eluent: dichloromethane / isopropanol, 99/1) to give 0.80 g of 4,9-dihydro-4,9-dioxo-2- (3-fluorophenyl) -thiazolo [ 4,5-g] quinoline as yellow crystals.

Yield: 30 i
F:> 260 C
Rf: 0.43 (CH2Cl2 / ethyl acetate, 80/20)
MS (IE): m / z 310 (M +)
1H NMR (CDCl3): # (ppm) 9.11 (d, 1H, H-7, JH6-H7 = 4.58Hz) 8.70 (d, 1H, H-5, JH5-H6 = 7.93Hz) 7.91 (m, 2H) , H-2 ', H-6') 7.78 (m, 1H, H-5 ') 7.53 (m, 1H, H-6) 7.31 (m, 1H, H-4')
13 C NMR (CDCl 3): # (ppm) 176.55 (2 C, C = O) 164.50 (1 C, C-3 ') 161.20 (1 C, C quat) 154.28 (1 C, C-7) 148.80 (1 C, C quat) 141.75 (1C, C quat) 135.71 (1C, C-5) 131.50 (1C, C-6) 129.40 (1C, Cquat) 127.05 (1C, C-5 ') 123.50 (1C, C-6') 129.40 (2C) , Cquat) 114.55 (2C, C-2 ', C-4')
IR (KBr): (cm-1) 1671 (C = O)
Example 5
4,9-Dihydro-4,9-dioxo-2- (4-fluorophenyl) thiazolo [4,5-g] quinoline
To 0.80 g (3.84 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxoquinoline is added at room temperature 5.53 g (23.02 mmol) of sulfide. of sodium nonahydrate dissolved in 9.6 ml of water. After 5 minutes, 4-fluorobenzaldehyde and 880 l of glacial acetic acid were added to the reaction medium, which had turned blue, 411 l (3.84 mmol). The reaction is maintained for 10 minutes at 800 ° C. and the brown precipitate that forms is filtered on sintered glass and then washed with ethanol. The brown solid thus obtained is taken up in 600 ml of chloroform and washed with 700 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness. The yellow product obtained is purified on cake (support: silica, eluent: dichloromethane / isopropanol, 99/1) to give 0.27 g of 4,9- dihydro-4,9-dioxo-2- (4-fluorophenyl) thiazolo [4,5-g] quinoline as yellow crystals.

Yield: 23%
F:> 2600C
Rf: 0.60 (CH2Cl2 / Methanol, 97/3)
MS (IE): m / z 310 (M +)
1H NMR (DMSO d6): δ (ppm) 9.09 (m, 1H, H-7) 8.54 (d, 1H, H-5, JHsH6 = 8.43Hz) 8.31 (m, 2H, H-2 ', H- 6 ') 7.95 (m, 1H, H-6) 7.46 (m, 2H, H-3', H-5 ')
IR (KBr): ρ (cm-1) 3052 (CH); 1678, 1667 (C = O)
Example 6 2- (2,4-Difluorophenyl) -4,9-dihydro-4,9-dioxothiazolo [4,5-g] quinoline
To 1.220 g (5.80 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxoquinoline, 4.220 g (17.50 mmol) of sodium sulphide nonahydrate are added at room temperature. solution in 21.6 ml of water. After 10 minutes, 0.64 ml (5.85 mmol) of 2,4-difluorobenzaldehyde and 1.33 ml of glacial acetic acid are added to the reaction medium which has become blue. The reaction is maintained for 4 hours at 80 ° C. and the precipitate black which is formed is filtered on sintered glass then washed with ethanol. The brown solid thus obtained is taken up in 250 ml of chloroform and washed with 150 ml of water. The organic phase is then dried over calcium chloride and evaporated to dryness. The yellow product obtained is purified on cake (support: silica, eluent: dichloromethane / isopropanol, 99.5 / 0.5) to provide 0.821 g of 2- (2,4-difluorophenyl) -4,9-dihydro 4.9 -dioxo-thiazolo [4,5-g] quinoline as yellow crystals.

Yield: 43%
F:> 2600C
Rf: 0.46 (CH2Cl2 / Methanol, 99/1)
MS (IE): m / z 328 (M +)
1H NMR (CDCl 3): δ (ppm) 9.11 (d, 1H, H-7, JH 6 -H 7 = 4.58Hz) 8.67 (m, 2H, H -5, H-6 ') 7.79 (m, 1H, H) -6) 7.09 (m, 2H, H-3 ', H-5')
13 C NMR (CDCl 3): δ (ppm) 177.02, 176.57 (2 C, C = O) 167.10 (1 C, C-2 ') 154.74 (1 C, C-7) 148.89 (1 C, C quat) 135.71 (1 C, C-C) 5) 131.54 (2C, Cquat) 129.85 (1C, C-6 ') 127.94 (1C, C-6) 113.21 (1C, Cquat) 113.17 (1C, C-5) 105.25 (1C, Cquat) 104.88 (1C, C) -3 ') 104.51 (1C, Cquat)
IR (KBr): (cm-1) 3071 (CH); 1683, 1670 (C = O)
Example 7
4,9-Dihydro-4,9-dioxo-2- (2-pyridyl) thiazolo [4,5-g] quinoline sulfate
200 mg (0.68 mmol) of 4,9-dihydro-4,9-dioxo-2
(2-pyridyl) -thiazolo [4,5-g] quinoline dissolved in 200 ml of chloroform, 56 μl (0.68 mmol) of sulfuric acid are added at 0 ° C. After stirring for 30 minutes at room temperature, the orange precipitate that forms is filtered on sintered glass, washed with ether and then with pentane to give 266 mg of 4,9-dihydro-4,9-dioxo-2- (2-sulfate) sulfate. pyridyl) -thiazolo [4,5-g] quinoline as orange crystals.

Yield: 100%
F:> 2600C
Rf: 0.48 (CH2Cl2 / Methanol, 98/2)
1H NMR (DMSO d6): δ (ppm) 9.05 (d, 1H, H-7, JH6 H7 = 4.58Hz) 8.76 (d, 1H, H-6 ', JH5'-H6' = 4.96Hz) 8.56 ( d, 1H, H-5, JH5-H6 = 7.94Hz) 8.33 (d, 1H, H-3 ', JH3'-H4' = 8.93Hz) 8.10 (m, 1H, H-4 ') 7.93 (m, 1H, H-6) 7.68 (m, 1H, H-5 ') 4.02 (Is, 1H, NH +)
IR (KBr): ρ (cm-1) 3392 (NH +); 1687, 1674 (C = O)
Example 8 4,9-Dihydro-4,9-dioxo-2- (3-furyl) -thiazolo [4,5-g] quinoline
To 2.00 g (9.6 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxoquinoline is added at room temperature 13.85 g (57.4 mmol) of sodium sulphide nonahydrate dissolved in 36 ml of water. After heating to 40 ° C., when the color of the solution changes from red to blue, 0.923 g (9.6 mmol) of furfural and then 2.74 ml of glacial acetic acid are added. After one hour of stirring, a slight brown precipitate forms. 100 ml of sodium carbonate (58) are then added to precipitate everything.The precipitate is filtered off, washed with water, dried and purified on a flash column (support: silica, dry deposit, eluent: dichloromethane / acetate). ethyl, 97.5 / 2.5). The yellow crystals obtained after evaporation of the solvents under reduced pressure are recrystallized after decolourization with animal black in methanol to give 0.308 g of 4,9-dihydro-4,9-dioxo-2-
(3-furyl) -thiazolo [4,5-g] quinoline as yellow crystals.

Yield: 11%
Rf: 0.43 (CH2Cl2 / ethyl acetate, 75/25)
MS (IE): m / z 282 (M +)
1H NMR (CD2Cl2): δ (ppm) 9.06 (dd, 1H, H-7, JH6-H7 = 4.58Hz, JH5-H7 = 1.83Hz) 8.61 (dd, 1H, H-5, JH5-H6 = 7.93 Hz, JH5-H7 = 1.83Hz) 8.30 (s, 1H, H-2 ') 7.75 (dd, 1H, H-6, JH5-H6 = 7.93Hz, JH6-H7 = 4.58Hz) 7.61 (m, 1H, H-5 ') 7.00 (m, 1H, H-4')
13 C NMR (CD 2 Cl 2): δ (ppm) 187.42 (1 C, C = O) 186.27 (1 C, C = O) 170.73 (1 C, C quat) 168.56 (1 C, C quat) 154.81 (1 C, C-7) 145.48 (1 C. , C-2 ') 144.53 (1C, C-5') 139.54 (1C, Cquat) 135.88 (1C, C-5) 128.29 (1C, C-6) 121.25 (1C, Cquat) 117.77 (1C, Cquat) 109.41 (1C, C-4 ') 102.29 (1C, Cquat)
IR (KBr): p 1683, 1655 (C = O)
Example 9
4,9-Dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4-g] quinoline
To 0.50 g (2.4 mmol) of 7-amino-6-chloro-5,8-dihydro-S, 8-dioxoquinoline is added at room temperature 3.45 g (14.4 mmol) of sodium sulphide nonahydrate dissolved in 6 ml of water. After stirring for 5 minutes at 400 ° C., 243 l (2.4 mmol) of benzaldehyde and 550 l of glacial acetic acid are added to the blue reaction medium. After 5 minutes at 400 ° C., the reaction medium is diluted with 1000 ml of chloroform.

The organic phase is extracted, washed 3 times with 400 ml of water, dried over calcium chloride and evaporated under reduced pressure. The powder thus obtained is purified on cake (support: silica, eluent: dichloromethane / methanol, 99/1) to give 0.25 g of 4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4- g] quinoline as yellow crystals.

Yield: 36%
F:> 260 0C
Rf: 0.53 (CH2Cl2 / Methanol, 98/2)
MS (IE): m / z 292 (M +)
1H NMR (CDCl3): δ (ppm) δ (d, 1H, H-6, JH6-H7 = 4.26Hz) 8.33 (d, 1H, H-8, JH7-H8 = 7.63Hz) 7.94 (d, 2H) , H-2 ', H-6', JH2'-H3 '= JH5'-H6' = 7.01 kHz) 7.52 (m, 1H, H-7) 7.31 (m, 3H, H-3 ', H- 4 ', H-5')
13 C NMR (CDCl 3): δ (ppm) 154.45 (1 C, C-6) 134.41 (1 C, C-8) 132.27 (1 C, C-7) 128.87 (2 C, C-3 ', C-5') 127.45 (2C, C-2 ', C-6') 127.09 (1C, C-4 ') 123.55 (1C, Cquat)
IR (KBr): δ (cm-1) 1687, 1654 (C = O)
Example 10
4,9-Dihydro-4,9-dioxo-2-) 2-fluorophenyl) -thiazolo
[5,4-g] quinoline
To 0.300 g (1.43 mmol) of 7-amino-6-chloro-5,8-dihydro-S, 8-dioxoquinoline, 2.073 g (8.63 mmol) of sodium sulphide nonahydrate are added at room temperature. solution in 6 ml of water. After stirring for 5 minutes at 40 ° C., 151 μl (1.41 mmol) of 2-fluorobenzaldehyde and 330 l of glacial acetic acid are added to the blue reaction medium. After 10 minutes at 55 ° C., the reaction medium is diluted with 1000 ml of chloroform. The organic phase is washed 3 times with 200 ml of water, dried over calcium chloride and evaporated under reduced pressure.The powder thus obtained is purified on cake (support: silica, eluent: dichloromethane / ethanol, 95/5) to give provide 0.400 g of 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo [5,4-g] quinoline as yellow crystals.

Yield: 90%
F:> 2600C
Rf: 0.56 (CH2Cl2 / Methanol, 98/2)
MS (IE): m / z 310 (M +)
1H NMR (cDCl3): δ (ppm) 9.14 (d, 1H, H-6, JH6-H7 = 4.88Hz) 8.61 (m, 2H, H-8, H-6 ') 7.75 (m, 1H, H) -7) 7.57 (m, 1H, H-4 ') 7.34 (m, 2H, H-3', H-5 ')
13 C NMR (CDCl 3): δ (ppm) 177.88 (1 C, C = O) 158.94 (1 C, C-2) 154.97 (1 C, C-6) 134.94 (1 C, C-8) 133.93 (1 C, C-7) ) 130.18 (1C, C-6 ') 127.61 (1C, C-4') 125.15 (1C, C-5 ') 116.50 (1C, C-3') 116.19 (1C, C-1 ')
IR (KBr): u (cm-1) 1693, 1659 (C = O)
Example 11
4,9-Dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4-f] isoquinoline
Synthesis of the intermediate 7-amino-6-chloro-5,8-dihydro-5,8-dioxoisoquinoline
To 8 20 g (0.036 mmol) of 6,7-dichloro-5,8-dihydro-5,8-dioxoisoquinoline suspended in 350 ml of acetic acid was added 3.74 g (0.057 mmol) of nitride. of sodium in solution in 16 ml of water. The reaction medium is stirred at 1000C for 2 hours. After cooling, 300 ml of ether are introduced. There is a precipitate that is filtered. This precipitate is purified on a flash column (support: silica, solid eluent deposit: ethyl acetate, 100%) to provide 5.34 g of 7-amino-6-chloro-5,8-dihydro-5,8- dioxo-isoquinoline.

Yield: 72%
1H NMR (CD2Cl2): δ (ppm) 9.32 (s, 1H, H-1) 9.25 (s, 2H, NH2) 9.00 (d, 1H, H-3, JH3-H4 = 4.89Hz) 7.82 (d, 1H, H-4, JH3-H4 = 4.88Hz)
IR (KBr): ρ (cm-1) 3354 (NH2); 1610, 1588 (C = O)
4,9-Dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4-f] isoquinoline (Example 11)
To 1020 g (5s7 mmol) of 7-amino-6-chloro-5,8-dihydro-5,8-dioxoisoquinoline was added all at once 831 g (34 mmol) of sodium sulphide nonahydrate dissolved in 42.5 ml of distilled water. After stirring for 1 hour at room temperature, 0 g59 ml (5 mmol) of benzaldehyde are added to the reaction mixture, which is then red, and then 31 ml of glacial acetic acid are added dropwise. After stirring for two hours, the mixture is extracted with chloroform. The organic phase is washed with water, dried over calcium chloride, filtered and evaporated to dryness. The product is then purified on a flash column
(support: silica, liquid deposit, dichloromethane / ethyl acetate, 80/20). After fading with animal black and recrystallizing from methanol, 50 g of 4,9-dihydro-4,9-dioxo-2-phenylthiazolo [5,4-f] isoquinoline are obtained in the form of yellow crystals.

Yield: 30%
Mp: 2380C
Rf: 0.56 (CH2Cl2 / ethyl acetate, 80/20)
MS (IE): m / z 292 (M +)
1H NMR (CD 2 Cl 2): δ (ppm) 9.51 (s, 1H, H-5) 9.12 (d, 1H, H-7, JH 7 -H 8 = 4.58Hz) 8.16 (dd, 2H, H-2 ', H -6 ', JH2'-H3' = JH5'-H6 '= 7.63Hz, JH2'-H4' = JH4'-H6 '= 1.83Hz) 8.00 (d, 1H, H-8, JH7-H8 = 4.58 Hz) 7.60 (m, 2H, H-3 ', H-5') 7.55 (m, 1H, H-4 ')
13 C NMR (CD 2 Cl 2): δ (ppm) 177.68 (2 C, C = O) 165.33 (1 C, C quat) 156.19 (1 C, C-7) 149.73 (1 C, C-5) 138.66 (1 C, C quat) 133.06 (1 C) , C-4 ') 132.27 (1C, Cquat) 129.41 (2C, C-3', C-5 ') 128.07 (2C, C-2', C-6 ') 118.97 (1C, C-8)
IR (KBr): δ (cm-1) 1684, 1659 (C = O)
Example 12
4,9-Dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo [5,4-f] isoquinoline
To 1.13 g (5.4 mmol) of 7-amino-6-chloro-5,8-dihydro-5,8-dioxoisoquinoline is added at room temperature 780 g (32 mmol) of sodium sulphide nonahydrate. in solution in 6 ml of water. After stirring for 4 hours at 45 ° C., 572 l (5.4 mmol) of 2-fluorobenzaldehyde and 1250 ml of glacial acetic acid are added to the blue reaction medium. After 5 minutes at 45 ° C., the mixture is allowed to come to room temperature and then the contents of the tricolor are poured into 1000 ml of chloroform. The organic phase is washed 3 times with 400 ml of water, dried over calcium chloride and evaporated under reduced pressure.

The powder thus obtained is purified on a cake (silica support, eluent: dichloromethane / ethyl acetate, 95/5) to give 40 g of 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [5,4-f] isoquinolin as yellow crystals.

Yield: 24%
F:> 2600C
Rf: 0.50 (CH 2 Cl 2 / ethyl acetate, 80/20) MS (IE): m / zm / z 310 (M +)
1H NMR (CD2Cl2): δ (ppm) 9.52 (s, 1H, H-5) 9.12 (d, 1H, H-7, JH7-H8 = 4.88Hz) 8.53 (m, 1H, H-6 ') 8.01 (d, 1H, H-8, JH7-H8 = 5.19Hz) 7.60 (m, 1H, H-4 ') 7.37 (m, 2H, H-3', H-5 ')
13 C NMR (CD 2 Cl 2): 6 (ppm) 156.31 (1 C, C-7) 153.83 (1 C, C quat) 149.85 (1 C, C-5) 138.84 (1 C, C quat) 134.60 (1 C, C-6 ') 130.14 ( 1C, C-4 ') 125.67 (2C, C-5', Cquat) 119.06 (1C, C-8) 116.98 (1C, C-3 ') 116.67 (1C, C-1')
IR (KBr): ν (cm-1) 1673 (C = O)
Example 13
4,9-Dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-f] isoquinoline
Synthesis of the intermediate 6-amino-7-chloro-5,8-dihydro-5,8-dioxoisoquinoline
In a suspension of 1700 grams (0.075 moles) of 6,7-dichloro-5,8-dihydro-5,8-dioxoisoquinoline in 500 ml of chloroform, a stream of ammonia was passed for 25 minutes. The reaction medium, which heats up from 26 ° C. to 50 ° C., is colored dark red and a precipitate appears. The excess of solvent is evaporated under reduced pressure and the solid residue obtained which contains an identical mixture 6-amino-7-chloro-5,8-dihydro-5,8-dioxoisoquinoline and 7-amino-6-chloro-5,8-dihydro-5,8-dioxoisoquinoline are washed with water, filtered, dried and then purified on a medium pressure column (support: silica, eluent dichloromethane / ethyl acetate, 80/20) to provide 0t203 g of 6-amino-7-chloro-5,8-dihydro-5,8-dioxo iso-quinoline.

Yield: 1. 3%
1H NMR (CD 2 Cl 2): δ (ppm) 9.37 (s, 2H, NH 2) 9.35 (s, 1H, H-1) 9.02 (d, 1H, H-3) 7.87 (d, 1H, H-4)
IR (KBr): ρ (cm-1) 3409 (NH2); 1632, 1614 (C = O)
4,9-Dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo
[4,5-f] isoquinoline (Example 13)
To 0.150 g (0.72 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxoisoquinoline, 1.040 g (4.3 mmol) of sodium sulfide nonahydrate in solution are added at room temperature. in 2.7 ml of water. After stirring for 2 hours at 50 ° C., 2-fluorobenzaldehyde and 164 μl of glacial acetic acid are added to the reaction medium which has become blue. After 20 minutes, the precipitate is filtered and washed 3 times. with 10 ml of water, dried and then purified on a flash column (support: silica, eluent dichloromethane / ethyl acetate, 80/20) to give 0.075 g of 4,9-dihydro-4,9-dioxo-2- ( 2-fluorophenyl) thiazolo [4,5-f] isoquinoline as yellow crystals.

Yield: 34%
F:> 2600C
Rf: 0.61 (CH2Cl2 / ethyl acetate, 80/20)
MS (IE): m / z 310 (M +)
1H NMR (CD2Cl2): δ (ppm) 9.44 (s, 1H, H-8) 9.14 (d, 1H, H-6, JH5-H6 = 4.88Hz) 8.51 (m, 1H, H-6 ') 8.08 (d, 1H, H-5, JH5-H6 = 5.19Hz) 7.60 (m, 1H, H-4 ') 7.37 (m, 2H, H-3', H-5 ')
13 C NMR (CD 2 Cl 2): δ (ppm) 178.47, 177.39 (2 C, C = O) 163.12 (1 C, C quat) 159.30 (1 C, C quat) 156.67 (1 C, C-6) 153.74 (1 C, C quat) 149.00 (1C) , C-8) 138.50 (1C, Cquat) 134.53 (2C, C-6 ', Cquat) 130.06 (1C, C-4') 126.22 (2C, C-5 ', Cquat) 119.87 (1C, C-5) 117.00 (1C, C-3 ') 116.69 (1C, C-1')
IR (KBr): δ (cm-1) 1687, 1658 (C = O)
Example 14
4,9-Dihydro-4,9-dioxo-2-phenyl-thiazolo [4,5-g] quinoxaline
Synthesis of the intermediary
6-amino-7-bromo-5,8-dihydro-5,8-dioxo-quinoxaline
To a solution of 4.0 g (12.5 moles) of 6,7-dibromo5,8-dihydro-5,8-dioxoquinoxaline in 160 ml of acetic acid is added 1.3 g (20.0 g). moles) of sodium nitride dissolved in 8.2 ml of water. The reaction medium is refluxed for 2 hours and changes from dark red to black. After complete cooling, 300 ml of ether are introduced. The precipitate thus formed is filtered and dried to provide 3.2 g of 6-amino-7-bromo-5,8-dihydro-5,8-dioxoquinoxaline as brown-red crystals.

Yield: 100%
MS (IE): m / z 254 (M +)
1H NMR (DMSO d6): 6 (ppm) 8.97, 8.95 (m, 2H, H-2, H-3)
4,9-Dihydro-4,9-dioxo-2-phenyl-thiazolo [4,5-g] quinoxaline (Example 14)
To 1.14 g (4.48 mmol) of 6-amino-7-bromo-5,8-dihydro-5,8-dioxoquinoxaline is added at room temperature 7.54 g (31.41 mmol) of sulfide of sodium nonahydrate in solution in 12 ml of water. After refluxing for one hour, 0.454 ml (4.48 mmol) of benzaldehyde and 1.250 ml of acetic acid are successively added. The black reaction mixture is refluxed for one hour. After complete cooling, the mixture is extracted with 300 ml of chloroform. The organic phase is washed with 100 ml of water, dried over calcium chloride and evaporated to dryness. The orange powder obtained is purified on cake (support: silica, eluent: dichloromethane / methanol, 100/0 to 99/1) to provide, after decoloration and recrystallization from dichloromethane, 0.50 g of 4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [4,5-g] quinoxaline as yellow crystals.

Yield: 38%
F:> 2600C
Rf: 0.55 (CH2Cl2 / Methanol, 97/3)
MS (IE): m / z 293 (M +)
1H NMR (CDCl3): δ (ppm) 9.09, 9.12 (2d, 2H, H-6, H-7, JH6-H7 = 2.14Hz) 8.19 (d, 2H, H-2 ', H-6') 7.58 (m, 3H, H-3 ', H-4', H-5 ')
13 C NMR (CDCl 3): δ (ppm) 178.55, 179.30 (2 C, C = O) 148.82, 148.40 (2 C, C-6, C-7) 145.07 (1 C, C quat) 133.06 (1 C, C-4 ') 131.59 (1C, Cquat) 129.46 (2C, C-2 ', C-6') 128.02 (2C, C-3 ', C-5')
IR (KBr): ν (cm-1) 1698, 1678 (C = O)
Example 4,9-Dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo- [4,5-g] quinoxaline
To 1.50 g (5.9 mmol) of 6-amino-7-bromo-5,8-dihydro-5,8-dioxoquinoxaline was added at room temperature 7.54 g (35.0 mmol) of sodium nonahydrate dissolved in 16.5 ml of water. After one hour of reflux, 0.632 ml (5.9 mmol) of 2-fluorobenzaldehyde and 1.650 ml of acetic acid are successively added. The black reaction mixture is refluxed for one hour and after complete cooling, extracted with 300 ml of dichloromethane. The organic phase is washed with 100 ml of water, dried over magnesium sulphate and evaporated to dryness. The orange powder obtained is purified on cake (support: silica eluent: dichloromethane / methanol, 100/0 to 99/1) to provide, after decoloration and recrystallization from dichloromethane, 0.70 g of 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-g] quinoxaline as yellow crystals.

Yield: 38 th
F:> 255 C
Rf: 0.60 (CH2Cl2 / Methanol, 97/3)
MS (IE): m / z 311 (M +)
1H NMR (CD2Cl2): δ (ppm) 9.06 and 9.04 (2d, 2H, H-6, H-7, JH6H7 = 2.14Hz) 8.52 (m, 1H, H-6 ') 7.99 (m, 1H, H) -5 ') 7.59 (m, 1H, H-4') 7.30 (m, 1H, H-3 ')
13 C NMR (CD 2 Cl 2): δ (ppm) 149.17, 148.82 (2 C, C-6, C-7) 134.71 (1 C, C quat) 134.58 (1 C, C quat) 130.10 (1 C, C-6 ') 125.65 (1C, C-4 ') 125.59 (1C, C-5') 116.94, 116.63 (2C, C-1 ', C-3')
IR (KBr): ν (cm-1) 1698, 1679 (C = O)
Example 16
4,9-dihydro-4,9-dioxo-2- (2-furyl) -7-methyl-thiazolo
[4,5-g] quinoline
To 1.50 g (6.75 mmol) of 6-amino-7-chloro-5,8-dihydro-5,8-dioxo-2-methyl-quinoline in solid form is added 9.73 g (40%). 50 mmol) of sodium sulphide nonahydrate dissolved in 25.2 ml of water. The mixture is left stirring for 6 hours at room temperature until a blue coloration appears. We add 584 ml
(6.75 mmol) furfural and then 1.93 ml (33.7 mmol) glacial acetic acid. The organic product is extracted with 5 times 500 ml of ethyl acetate. The organic phases are combined, washed with water, dried over magnesium sulphate, filtered and evaporated under reduced pressure. 0.70 g of light brown solid product is obtained which is purified on a flash column (support: silica eluent: dichloromethane / isopropanol, 100/0 to 99.75 / 0.25) to provide, after decolorization, 0.31dihydro-4,9-dioxo-2- (2-furyl) -7-methyl-thiazolo [0.31 g]; 4,5-g] quinoline as yellow-orange crystals.

Yield: 16.3%
F:> 260 C
Rf: 0.50 (CH2Cl2 / Methanol, 99/1)
MS (IE): m / z 296 (M +) 1H NMR (CD2Cl2): δ (ppm) 8.46 (d, 1H, H-5, JH5 H6 = 7.94Hz) 7.71 (d, 1H, H-5 ') 7.60 (d, 1H, H-6, JH5-H6 = 8.24Hz) 7.43 (d, 1H, H-3 ') 6.69 (m, 1H, H-4') 2.77 (s, 3H, CH3)
13 C NMR (CD 2 Cl 2): δ (ppm) 181.0 (1 C, C = O) 146.7 (1 C, C-5 ') 135.9 (1 C, C-5) 128.1 (1 C, C-6) 114.2 (1 C, C) 3 ') 113.7 (1C, C-4') 25.3 (CH 3)
IR (KBr): δ (cm-1) 1723, 1685 (C = O)
Example a
4,9-Dihydro-4,9-dioxo-2-phenyl-1H-imidazo [4,5-g] quinoline
Reference: CA 59 P13957a
Yield: 71%
F:> 2600C
Rf: 0.50 (CH2Cl2 / Methanol, 90/10)
MS (IE): m / z 275 (M +)
1H NMR (DMSO d6): δ (ppm) 14.48 (bs, 1H, NH) 9.99 (m, 1H, H-7) 8.45 (d, 1H, H-5, JH5-H6 = 7.33Hz) 8.24 (m) , 2H, H-2 ', H-6') 7.83 (m, 1H, H-6) 7.61 (m, 3H, H-3 ', H-4', H-5 ')
13 C NMR (DMSO d 6): δ (ppm) 153.26 (1 C, C-7) 148.50 (1 C, C quat) 134.25 (1 C, C-5) 130.08 (1 C, C quat) 129.25 (2 C, C-3 ', C) -5 ') 127.45 (1C, C-6) 125.43 (1C, C-4') 116.24, 115.92 (2C, C-2 ', C-6')
IR (KBr): (cm-1) 3232 (NH); 1669, 1650 (C = O)
Example b
4,9-Dihydro-4,9-dioxo-2-phenyl-oxazolo [4,5-g] quinoline
Reference: CA 115 256051q
Yield: 61%
F:> 2600C
Rf: 0.45 (CH2Cl2 / Methanol, 95/5)
MS (IE): m / z 276 (MH +)
1H NMR (CDCl 3): δ (ppm) 8.80 (d, 1H, H-7, JH 6 -H 7 = 4.00Hz) 8.44 (d, 1H, H-5, JH 5 -H 6 = 8.18Hz) 8.13 (d, 2H) , H-2 ', H-6', JH2'-H3 '= JH5'-H6' = 7.63Hz) 7.56 (m, 1H, H-6) 7.35 (m, 3H, H-3 ', H-4) ', H-5')
13 C NMR (CDCl 3): δ (ppm) 176.40, 170.68 (2 C, C-4, C-9) 154.15 (1 C, C-7) 147.65 (1 C, C quat) 134.93 (1 C, C-5) 132.90 (1C, C-6) 129.07 (1C, Cquat) 128.81 (2C, C-3 ', C-5') 127.95 (2C, C-2 ', C-6') 127.28 (1C, C-4 ') 124.38 (1C, Cquat)
IR (KBr): ν (cm-1) 1665, 1623 (C = O)
Example c 4,9-Dihydro-4,9-dioxo-2-phenyl-thiazolof-4,5-gl-quinoline
Reference: CA 54 500g
Yield: 36%
F:> 2600C
Rf: 0.55 CH2Cl2 / Methanol, 98/2)
MS (IE): m / z 292 (M +)
1H NMR (CDCl3): δ (ppm) 9.09 (d, 1H, H-7, JH6-H7 = 4.88Hz) 8.65 (d, 1H, H-5, JH5-H6 = 8.43Hz) 8.17 (d, 2H) , H-2 ', H-6') 7.75 (m, 1H, H-6) 7.61 (m, 3H, H-3 ', H-4', H-5 ')
13 C NMR (CDCl 3): δ (ppm) 176.55 (2C, C = O) 154.48 (1C, C-7) 148.80 (1C, Cquat) 135.81 (1C, C-5) 132.71 (1C, C-6) 131.79 129.81 (2C, C quat) 129.36 (2C, C-3 ', C-5') 127.87 (3C, C-2 ', C-4', C-6 ')
IR (KBr): ρ (cm-1) 3051 (NH); 1665 (C = O)
Example of
4,9-Dihydro-4,9-dioxo-2- (2-pyridyl) -thiazolo [4,5-g] quinoline
Reference: CA 55 19008b
Yield: 27%
F:> 2600C
Rf: 0.52 (CH2Cl2 / Methanol, 97/3)
MS (IE): m / z 293 (M +)
1H NMR (CDCl3): δ (ppm) 9.04 (d, 1H, H-7, JH6-H7 = 4.88Hz) 8.63 (m, 2H, H-5, H-6 ') 8.40 (d, 1H, H) -3 ', JH3'-H4' = 7.93Hz) 7.81 (m, 1H, H-4 ') 7.70 (m, 1H, H-6) 7.42 (m, 1H, H-5')
13 C NMR (CDCl 3): δ (ppm) 154.06 (1 C, C-7) 149.47 (1 C, C-6 ') 148.39 (1 C, C-2') 143.80, 142.33 (2 C, C quat) 136.33 (1 C, C -4 ') 135.30 (1C, C-5) 134.10, 132.30 (2C, Cquat) 126.29 (1C, C-6) 127.40 (1C, C-3') 120.25 (1C, C-5 ')
IR (KBr): ρ (cm-1) 3059 (CH); 1665 (C = O)
Example e
4,9-Dihydro-4,9-dioxo-2- (3-pyridyl) -thiazolo [4,5-g] quinoline
Reference: CA 58 P5695e
Yield: 39 E
F:> 2600C
Rf: 0.43 (CH2Cl2 / Methanol, 95/5)
MS (IE): m / z 293 (M +)
1H NMR (CDCl 3): δ (ppm) 9.36 (s, 1H, H-2 ') 9.12 (d, 1H, H-7, JH 6 -H 7 = 3.06Hz) 8.82 (d, 1H, H-6', JH5'-H6 '= 3.96Hz) 8.72 (m, 1H, H-5) 8.48 (d, 1H, H-4', JH4'-H5 '= 7.93Hz) 7.79 (m, 1H, H-6) 7.51 (m, 1H, H-5 ')
13 C NMR (CDCl 3): δ (ppm) 177.55, 178.43 (2 C, C = O) 172.50 (1 C, C quat) 154.68 (1 C, C-7) 153.15, 148.70 (2C, C-2 ', C-6') ) 135.91 (1C, C-5) 134.93 (1C, C-4 ') 129.81 (1C, Cquat) 128.07 (1C, C-6) 124.08 (1C, C-5)
IR (KBr): ρ (cm -1) 1671 (C = O)
Pharmacological properties
The study of the compounds of the present invention and their possible salts has demonstrated that they possess various pharmacological properties.Thus, they are selectively veinotonic, affecting the arterial system only at concentrations much higher than those active on the veins except for certain arteries, especially cerebral arteries. The compounds show no affinity or a very low affinity for known membrane pharmacological receptors. Moreover, they increase the capillary resistance, decrease the vascular hyperpermeability induced by certain inflammatory agents.

 These properties are demonstrated in mammals such as hamsters, rats, guinea pigs and rabbits, under in vitro conditions (vessels or isolated vascular networks) and in vivo.

For in vitro studies, the compounds are solubilized in pure aqueous solution or containing DMSO
(Dimethylsulfoxide).

 For in vivo studies, they are administered intravenously or intraperitoneally in the form of an aqueous solution containing or not DMSO, or orally suspended in 1% carboxymethylcellulose, administered with the aid of a feeding tube under a volume of 10 ml / kg.

Pharmacological study models
Contractile effects
The contractile effects are measured in vitro under static conditions on capacitance or resistance vascular rings of saphenous, femoral, jugular, mesenteric, cellar veins ... and on femoral, carotid, basilar, mesenteric, thoracic or abdominal aortic arteries. rat (Wistar, 200 to 250 g), rabbit (New Zealand, 2 to 2.5 kg), guinea pig (Dunkin Hartley 250 to 300 g).

 The rings are placed in an isolated organ chamber (25 ml for capacitance vessels and 2.5 ml for Mulvany resistance vessels), maintained under isometric conditions by two rigid wires inserted into the vessel, avoiding damage to the endothelium. The vessels are bathed with a modified Krebs solution (in mM: NaCl = 118, KCl = 4.6, CaCl2 = 2.5, MgSO4 = 1.2, KH2PO4 = 1.17, NaHCO3 = 25, glucose = 11). , permanently aerated with a gaseous mixture at 95 e 2 and 5% CO2, at pH = 7.4 and thermostated at 37 ° C.

The rings are brought to their optimum point of the voltage-length relationship.

The developed voltages generate an electrical signal via a force sensor (bridge of
Wheatstone). This signal is amplified before being visualized on Kipp & Zonen recorder, or digitized to be processed by computer (IOS, EMKA). Pharmacological studies are carried out after some preliminary contractile stimulations standardized by a depolarizing solution (hyperpotassium obtained by replacing NaCl with KCl in equimolar quantities), rinses and periods of equilibration in pure physiological solution. The presence of endothelium is verified by the relaxation induced by increasing concentrations of acetylcholine after stabilization of vascular precontraction.

 The contraction forces developed by the vascular rings in response to the different compounds are studied on quiescent vessels or electrically stimulated (5-8 Hz), by a hyperpotassium depolarizing "physiological" solution (Kcl: 20, 40 mM), by norepinephrine (increasing concentrations), serotonin (increasing concentrations) ...

 The contractions are expressed in mg force or as a percentage of the maximum contraction to depolarization by a hyperpotassium "physiological" solution.

 The contractile effects are also measured in vitro under dynamic flow conditions, by the pressure developed by vascular networks perfused at a constant rate. At the mesenteric level, the venoselectivity is studied on the model of simultaneous double perfusion and separated from the arterial and venous networks, model developed by T. WARNER (British J. Pharmacol.

1990, 99, 427-433). The separation of the two networks is achieved by cutting the vessels and tissues along the intestinal border. The networks are perfused at 2 ml.min -1 with a Krebs solution (37.50C) aerated at 95% 2 and 5 t CO2.

 In vivo, arterial and venous pressures are measured in the anesthetized animal under basal conditions and after circulatory arrest caused by swelling of a balloon catheter introduced into the right atrium. In cardiac arrest, venous tone (mean circulatory filling pressure at constant blood volume) is calculated from venous and arterial pressures measured at equilibrium and corrected for relative differences in compliance between these two networks (SAMAR & COLEMAN, Am. J.

Physiol. 1978, 234: H94-100; Yamamoto et al., Am. J. Physiol. 1980, 238: H823-828).

In aroused animals, arterial pressures are measured according to the classical method derived from Riva
Rocci, by analysis of the acoustic wave transmitted at the arterial level and transformed by a ceramic piezo transducer placed on the tail of the rat, downstream of a sleeve inflated automatically by a pressure generator
At the microcirculatory level, venular and arteriolar sectional variations are studied in vivo in the model of the hamster dorsal skin chamber, after videomicroscopic recording.
(Leitz Ergolux microscope equipped with a halogen source for lighting and a black and white CDD video camera
HPR 610) and computer analysis (Visicap software, Pack
ICAP) images.

 After pentobarbital sodium anesthesia (60 mg / kg i.p.), the back of the animal is shaved and shaved so that an observation chamber can be placed (Prof.

GEBHARD, Heidelberg) on the skin of the back. Both parts of the chamber are sewn after carefully removing the skin thicknesses that may interfere with the observation. A jugular catheter is placed for the i.v. administration of the products, 48 hours after the operation.

Effects on induced capillary hyperpermeability
Vascular permeability is studied in vivo by measuring the extravasation of albumin, the amount of which is determined by an albumin binding dye (Blue
Evans). Hyperpermeability is induced by intradermal injection of a solution of histamine, bradykinin or zymosan.

 The technique is derived from that described by BEACH & STEINETZ, J. Pharmacol. Exp. Therap., 1961, 131: 400406.

 The rats (Wistars, 200 to 230 g) are shaved on their abdominal wall one hour before the start of the experiment. The product to be tested is injected i.p. or per os 1 hour to 4 hours before the sacrifice. The rats are anesthetized with a mixture of halothane. Then, they receive an intradermal injection on the abdomen of 0.10 or 0.15 ml (either for histaline 6.7 or 10 micrograms) of inflammatory agent and an intravenous injection of one ml of a solution of Evans Blue 0.5% in the vein of the penis. These injections are performed 30 minutes before euthanasia.

 30 minutes after these two injections, the rats are euthanized by cervical dislocation.

 At the point of injection of the inflammatory agent, the skin is cut and placed in glass tubes with a sterile neck containing 3 ml of fuming hydrochloric acid. Digestion of the skin is achieved by contact for at least one hour in a water bath at 370C. Three ml of 12.8 E benzalkonium chloride are then added. After standing for 30 minutes, 7 ml of dichloromethane are added. The tubes are stirred periodically for one hour. The aqueous phase is removed by suction and the organic phase "dichloromethane" is filtered. Optical densities are quantified by absorption spectrophotometry at a wavelength of 620 nm against a blank containing only dichloromethane.

 The averages of the optical densities of the different batches of treated or control animals are calculated, then a percentage variation of the values corresponding to the treated animals compared to those of the control animals is calculated.

The effect of the compounds on the hyperpermeability induced by inflammatory agents, such as histamine and bradykinin, is also studied after intravenous bolus injection in the dorsal hamster cutaneous chamber model and according to the method developed by GIMENO et al. previously described (A new technique using intravital videomicroscopy for macromolecular permeability measurement, 18 European Microcirculation Congress,
Rome 1994) by videomicroscopy and image analysis by quantification of the distribution of intravenous and extravascular fluorescence marker (FITC-Dextran) injected bolus by the jugular catheter (63 mg / kg for a defined volume of 1 ml / kg The microscope is equipped with a fluorescent source and a combination of filters
(excitation in blue 450-490 nm and stop filter 515 nm).

Effects on capillary resistance
The increase of the capillary resistance is appreciated by the modification of the petechial index (negative pressure inducing the extravasation of the erythrocytes), measured by a method derived from the angiosterrometer of Parrot.

 The study is performed on male Wistar rats with an average weight of 200 g (approximately six weeks old). The lower back region is shaved and then depilated with a paste based on a thioglycolic acid derivative and calcium hydroxide. After about thirty minutes, the skin is thoroughly rinsed and dried.

 On the day of the study, the rats are kept unconstrained. A depression of 80 mm of mercury is applied. If the petechiae (extravasation of erythrocytes) have not appeared within 15 seconds, the depression is increased by compensating by holding the suction cup in the same place.

 The minimum depression for which petechiae occur expresses, in mm of mercury, the basic capillary resistance value (before any treatment). Two measurements are made for each test at different locations of the back.

 The rats are treated orally. After a fixed time (usually 2, 4, 6 hours) following the treatment, the test is repeated on different skin areas, until the appearance of petechiae, providing a new index of depression. All measurements are blind.

 A percentage of variation of the capillary resistances of the treated animals with respect to their basic capillary resistance is calculated for each compound studied at each treatment time and compared with the control group (excipient alone) or the reference group.

Effects on induced pleurisy in rats
The anti-inflammatory activity of the compounds is also studied by measuring the inhibition of edema and leukocyte migration after induction of pleurisy in the rat by injection of carrageenin into the pleural cavity (ALMEIDA et al., J. Pharmacol Exp Therap., 1980, 214: 74).

 Rats are treated per os by the compounds 2 hours before the injection of carrageenin, as well as 2 and 4 hours after this injection. After a determined time (6 hours) following the induction of pleurisy, the rats are euthanized and the pleural fluid recovered by aspiration and its volume is measured. Leukocyte cells are counted by "cell counter".

 The results are expressed as the number of leukocytes in the exudate relative to 100 g of weight of the animal and compared to those of the control group.

Examples of pharmacological effects
The compounds of the invention and their optional salts selectively increase, in the majority of cases, the contraction of the animal veins produced by norepinephrine, by electrical stimulation or by a depolarizing hyperpotassium solution.

By way of illustration, the contractile effect of different compounds on the saphenous vein of the rabbit preconcerted by a depolarizing "physiological" solution of potassium concentration equal to 40 mM is shown; the maximum effect produced by each compound is expressed as a percentage of the maximum contraction induced by depolarizing hyperpotassium solutions and as an ED50 value) ::
Emax compounds (% Contr.max.) ED50 (nM)
Example c 23 + 4 140
Example e 28 + 6 160
Example 1 il + 3,600
Example 3 21 + 3 113
Example 5 39 + 8 100
Example 8 17 + 5 126
Example 10 30 + 8 45
Example 12 36 + 8 22
Example 14 18 + 3 150
By way of illustration, the oral administration of certain compounds of the invention and of their optional salts increases the capillary resistance of the rat at doses generally ranging between 0.01 and 5 mg / kg.
Compounds Effect at 4 o'clock Effect at 6 o'clock
(in% of the control) (in% of the control)
Example c 5 mg / kg 23 19
Example of 5 mg / kg 21 23
Example 6 5 mg / kg 23 21
Example 7 5 mg / kg 31 24
Example at 0.1 mg / kg 42 33
Example b 0.1 mg / kg 21 13
Example e 0.1 mg / kg 34 17
Example 2 0.1 mg / kg 23
Example 3 0.1 mg / kg 24 26
Example 4 0.1 mg / kg 17 17
Example 14 0.1 mg / kg 19 23
By way of illustration, oral administration of certain compounds of the invention and of their optional salts reduces the inflammatory hyperpermeability induced by zymosan in the rat at doses of between 0.1 and 5 mg / kg.
Compounds Effect at 2 hours Effect at 4 hours
(in% of the control) (in% of the control)
Example of 5 mg / kg -23 -7
Example at 0.1 mg / kg 9 -41
Example b 0.1 mg / kg -5 -23
Example 4 0.1 mg / kg 3 -37
Example 10 0.1 mg / kg -7 -14
Example 15 0.1 mg / kg -14 -17
Moreover, the compounds of the invention and their possible salts are very little toxic. For example, after a single oral administration of 500 mg / kg in the mouse, no observable toxic effect and no mortality was observed for the majority of the compounds in particular for Example c, Example d, Example 2 Example 3 (orange urine), Example 5.

 Most of the compounds are found to be non-cytotoxic (cell viability being measured by quantification of neutral red cell incorporation) to concentrations equal to their aqueous solubility on mouse fibroblast cell lines (L929), in particular Example c, Example 3, Example 4, Example 6.

 Among the preferred compounds of the invention, Example 3 is particularly preferred.

 The above shows that the compounds of the invention and their possible salts can be used in human and animal therapy. They are particularly indicated in functional venous insufficiency, organic and hemorrhoidal pathologies by their vascular and anti-inflammatory components, as well as in typically inflammatory conditions and in shock states constituted by a significant fall in blood pressure. In the latter case, an improvement in venous return is likely to maintain cardiac output and consequently consequently arterial pressure.

 Functional venous insufficiency is characterized by dilatation and hyperdistensibility of the superficial veins of the lower limbs, oedemas, paresthesia like impatience, restless leg. This type of pathology can progress to organic venous insufficiency characterized by the development of varicose veins, valvular incontinence, or even phlebothrombosis and trophic disorders leading to ulcerous lesions.

 In this venous pathology, an inflammatory component settles in the early stages and is manifested more clearly in the advanced stages.

 By their venoconstrictor, anti-inflammatory effects, in particular on vascular hyperpermeability and their contractile effects on the cerebral arteries, the compounds of the invention and their possible salts are also indicated in migraine.

 The present invention therefore comprises the use of the compounds mentioned above and their optional salts, as active substances for the preparation of medicaments and pharmaceutical compositions for human and veterinary use, comprising at least one of said compounds and salts in combination with a physiologically acceptable carrier or diluent.

The form of these drugs and pharmaceutical compositions will obviously depend on the desired route of administration including oral, parenteral, topical
(cutaneous) and rectal, and they can be formulated according to conventional techniques with implementation of carriers and conventional vehicles.

 Thus, in the case of oral administration, they may be in the form of tablets, tablets, capsules, solutions, syrups, emulsions, suspensions, powder, granules, soft capsule, lyophilizate, microcapsule, microgranule.

 Tablets, tablets and capsules contain the active substance together with a diluent (eg lactose, dextrose, sucrose, mannitol, maltitol, xylitol, sorbitol or cellulose), a lubricant (eg silica, talc or stearate), a binder (eg starch, methylcellulose or gum arabic), a disintegrating agent (alginate for example) and they are manufactured by known techniques, for example mixing, granulating, pelletizing, coating, compression, etc.

 The syrups may contain, as carrier, glycerol, mannitol and / or sorbitol. Solutions and suspensions may include water and other physiologically compatible solvents and a carrier such as a natural gum, agar, sodium alginate or polyvinyl alcohol.

 For parenteral administration, the drugs and compositions may take the form of solutions, emulsions or suspensions comprising the active substance and a suitable carrier or solvent such as sterile water or sterile isotonic saline solutions.

 For dermal application, the drugs and compositions may take the form of ointment, cream or gel, in the form of emulsion or suspension, solution, foam, powder.

 For rectal application, the drugs and compositions may take the form of capsule, cream, emulsion, gel, mousse, ointment, suppository.

Claims (24)

 1. Use of nitrogen tricyclic derivatives and pharmaceutically acceptable salts thereof according to the general formula

 in which  A is either a sulfur atom, oxygen atom, or an R3N radical where R3 is a hydrogen atom, a C1-C8 alkyl radical, a substituted or unsubstituted aromatic ring, or a substituted or unsubstituted heteroaromatic ring,  X1, X2, X3, X4 are independently of one another a carbon atom or a nitrogen atom,  R1 is a C1-C8 alkyl radical, a substituted or unsubstituted aromatic ring, or a heteroaromatic ring, having one or more heteroatoms, substituted or unsubstituted,  R2 is a hydrogen atom, a C1-C5 alkyl radical, for obtaining a medicament for the treatment of diseases related to an impairment of venous function and / or inflammatory edema.  2. As a new product, 4,9-dihydro-4,9-dioxo-2- (4-fluorophenyl) -1H-imidazo [4,5-g] quinoline.  3. As a new product, 4,9-dihydro-4,9-dioxo-2- (3-pyridyl) -1H-imidazo [4,5-g] quinoline.  4. As a new product, 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) thiazolo [4,5-g] quinoline.  5. As a new product, 4,9-dihydro-4,9-dioxo-2- (3-fluorophenyl) thiazolo [4,5-g] quinoline.  6. As a new product, 4,9-dihydro-4,9-dioxo-2- (4-fluorophenyl) thiazolo [4,5-g] quinoline.  7. As a novel product, 2- (2,4-difluorophenyl) -4,9-dihydro-4,9-dioxothiazolo [4,5-g] quinoline.  8. As a new product, 4,9-dihydro-4,9-dioxo-2- (2-pyridyl) -thiazolo [4,5-g] quinoline sulfate.  9. As a new product 4,9-dihydro-4,9-dioxo-2- (3-furyl) -thiazolo [4,5-g] quinoline.  10. As a new product, 4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4-g] quinoline.  11. As a new product, 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo [5.4-g] quinoline.  12. As a new product, 4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [5,4-f] isoquinoline.  13. As a new product, 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo [5,4-f] isoquinoline.  14. As a new product, 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo [4,5-f] isoquinoline.  15. As a new product 4,9-dihydro-4,9-dioxo-2-phenyl-thiazolo [4,5-g] quinoxalin  16. As a new product 4,9-dihydro-4,9-dioxo-2- (2-fluorophenyl) -thiazolo [4,5-g] quinoxaline.  17. As a new product, 4,9-dihydro-4,9-dioxo-2- (2-furyl) -7-methyl-thiazolo [4,5-g] isoquinoline.  18. As intermediate, 7-amino-6-chloro-5,8-dihydro-5,8-dioxoisoquinoline.  19. As intermediate, 6-amino-7-chloro-5,8-dihydro-5,8-dioxoisoquinoline.  20. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament for the treatment of functional and organic venous insufficiency.  21. Use of the compounds according to any one of claims 1 to 17 for obtaining a drug for the treatment of hemorrhoidal pathologies.  22. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament for the treatment of migraine.  23. Use of the compounds according to any one of claims 1 to 17 for obtaining a medicament for the treatment of dermatological and cardiovascular osteoarticular inflammations.  24. Use of the compounds according to any one of claims 1 to 17 for obtaining a drug for the treatment of shock states consisting of a significant drop in blood pressure especially in septic shock states.